All breast cancers are not the same, so it makes sense that treatments can no longer be one-size-fits all. However, once a treatment regimen is in place and becomes standard, it can take a long time to remove it from practice, even when scientific evidence no longer supports its use.
Many women diagnosed with invasive breast cancer of different subtypes continue to receive the same adjuvant chemotherapy regimen, one including a controversial class of drugs called anthracyclines, though evidence shows that the drugs may only provide benefit to a small group of patients, and could be replaced with a less toxic substitute.
The class of chemotherapy drugs called anthracyclines includes doxorubicin (Adriamycin®) and epirubicin (Ellence®). Side effects include short term nausea and hair loss and potential long-term effects such as heart damage (1-2% of patients) and leukemia (less than 1% of patients) (Barlett-Lee, 2009).
Bevacizumab (Avastin®) is the first cancer therapy approved by the Food and Drug Administration (FDA) to inhibit angiogenesis, which refers to the development of new blood vessels needed to carry vital nutrients to a tumor. Bevacizumab inhibits angiogenesis by blocking “Vascular Endothelial Growth Factor” or VEGF (pronounced Veg-F), a protein that is excessively produced by tumor cells and a key factor in the growth of many types of cancer.
This therapeutic agent is a monoclonal antibody, a type of highly specific antibody created in the laboratory that selectively binds to substances in the body, including cancer cells. Each monoclonal antibody is created to find and bind to one specific substance. Bevacizumab selectively binds to VEGF, blocking the protein’s ability to bind to its receptors on the surface of endothelial cells, which are the main cells in the inside lining of blood vessels. By blocking the activity of VEGF, bevacizumab can reduce the development of blood vessels and the delivery of oxygen and nutrients needed by the tumor to grow and spread.
Non-invasive in situ carcinoma is a condition where abnormal cells are found within the milk ducts or lobules and have not spread to the surrounding tissues in the breast or other parts of the body.
In the United States in 2011, 230,480 women were diagnosed with invasive breast cancer and an estimated 57,650 women were diagnosed with non-invasive in situ carcinoma (ACS, 2011). Of these cases, about 85% will be ductal carcinoma in situ (DCIS), meaning the abnormal cells are contained within the milk ducts, and approximately 15% are lobular carcinoma in situ. The terms are misleading however, as these lesions are not cancer. Incidence rates of in situ carcinoma increased rapidly during the 1980s and 1990s with widespread use of mammography screening, and this increase was the largest in women aged 50 and older (Howlader, 2011). The incidence of DCIS increased over seven-fold from 1980 to 2007, from 4.8 per 100,000 to 34.6 per 100,000. Since 2004, incidence rates of in situ breast cancer have been stable in white women and increasing in black women by 2.0% per year (ACS, 2012). Today, approximately one woman is diagnosed with DCIS for every four women diagnosed with invasive breast cancer (Allegra, 2010).
Although DCIS is a risk factor for invasive breast cancer, the natural history of DCIS and the likelihood that DCIS will progress to invasive disease is unknown. There is no available data on DCIS that is left untreated. However, a review of autopsy records showed that somewhere between 9% and 15% of women have undetected DCIS at death (Welch, 1997). This supports the idea that a proportion of DCIS occurrences will not progress into invasive cancer or become life-threatening. The problem is that we do not know how to identify this proportion yet.
How best to treat DCIS, and even whether to consider it cancer, remain controversial.
HER2 (also Her-2/neu or ErbB2) stands for Human Epidermal Growth Factor Receptor 2, and is one of a family of several receptor proteins. All normal breast cells contain the HER2 gene, which gives instructions to the cell on how to make the HER2 protein. The HER2 protein, also called a HER2 receptor, helps to send signals to the inside of the cell telling it to grow and divide. Breast cancer cells that are HER2-positive have extra copies of the HER2 gene and produce extra HER2 receptor proteins. Too much HER2 protein is thought to cause cancer cells to grow and divide more quickly.
Trastuzumab (Herceptin®) has been used to treat more than 420,000 women with HER2-positive breast cancer worldwide (Genentech Inc., 2010). Heralded as a major advance in targeted cancer therapies when first introduced, the drug has been included in breast cancer treatment protocols in the U.S. since receiving approval for use by the Food and Drug Administration (FDA) in 1998. Despite widespread use and extensive research, however, the mechanism by which trastuzumab acts is not completely understood (National Cancer Institute, 2010). And many questions about which patients will get the most benefit from trastuzumab and the optimal treatment protocols remain unanswered.
A great deal of attention and resources have focused on the area of early detection. A mantra that has been drummed into our consciousness over the past forty years is that early detection saves lives. The reality is otherwise. About 70% of women in this country over age 40 have had a mammogram in the last two years. The evidence of a mortality reduction from screening is conflicting and continues to be questioned by some scientists, policy makers, and members of the public. The analyses to date of all randomized controlled trials for mammography have concluded marginal benefit (Gotzsche, 2011; USPSTF, 2009).
For more information, read NBCC’s position paper on mammography screening.
We know that not all breast cancers are the same. Though we have known for some time that some breast cancers express excess estrogen receptors, we now know that there are several types of breast cancer based on the biology of the tumors. These subtypes respond to different treatments and have different prognoses. Though more will likely be identified in the future, breast tumors are currently classified using five immunohistochemical (IHC) tumor markers: estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER-2), HER-1, and cytokeratin 5/6 (CK 5/6) (Carey, 2006). Based on expression of these markers, breast tumors are classified into the following subtypes: luminal A (ER+ and/or PR+, HER-2-); luminal B (ER+ and/or PR+, HER-2+); HER-2+ (and ER-, PR-); basal-like (ER-, PR-, HER-2-, HER-1+, and/or CK 5/6+); and normal (negative for all five markers) (O’Brien, 2010).
Approximately 70% of “triple negative” breast cancers (TNBC) are basal-like, therefore triple negative is often used as a surrogate for basal-like subtype (Bertucci, 2008; Bidard, 2007). These different subtypes of breast cancer behave differently, are associated with different populations of women and different risk factors, and may have different causes. However, current annual incidence and mortality statistics are reported for breast cancer overall and not by subtype.
Women do not die of primary breast cancer. Over 90% of breast cancer deaths are due to the spread of the disease to other parts of the body, such as bone, lungs, liver and brain. Approximately 162,000 women are living with metastatic breast cancer in the United States, according to one expert. However, the exact numbers are neither collected nor maintained, and we do not have information on historical trends.
Close to one-third of the women considered “cured” of breast cancer will suffer recurrences and metastatic spread of the disease, often many years after their initial diagnosis. While researchers have identified treatments that sometimes shrink or slow metastatic tumors, such as estrogen blockers, radiation and chemotherapy, they are most often temporary. Treatments to eradicate metastasis do not exist. There is no cure.
Though preventing breast cancer metastasis is crucial to decreasing the mortality from breast cancer, the ultimate goal is to prevent breast cancer development all together, to avoid not only the mortality from the disease, but also the mortality and morbidity from treatments for the disease.
Though the increasing focus on the development of targeted treatments may lead to more efficacious and less toxic treatments, we will not make more than incremental progress over the next eight years unless we shift some resources to understanding the causes of breast cancer and learning how to prevent development of the disease. NBCC is doing just that through the Primary Prevention summit and workshops and the Artemis Project®.